The proposed research is directed toward the discovery of novel peptide inhibitors of platelet adhesion to the inflamed endothelium that would have value in the prevention and treatment of atherosclerosis, thrombosis, stroke, and heart attack. The novel mechanism addressed is inhibition of the F11 receptor (F11R;aka JAM-A), a cell adhesion molecule found on the surface of human platelets and in the vascular endothelium. F11R is critical for the adhesion of platelets to inflamed blood vessels. Two peptide leads (peptides 1 and 4) derived from the F11R sequence have been shown to inhibit F11R activity. The sequences of these peptides are found in close proximity on the F11R protein surface, suggesting that both sequences are involved in the interaction during adhesion. Free peptides 1 and 4 inhibit the association and are thought to interact with F11R to block the cell-adhesion. Extensive work has validated the activity of these peptides in models of platelet activity, however, these leads are long peptides (14 and 23 amino acids), lacking proteolytic stability, and there has been no systematic study of peptide structure-activity relationships and the requirements for biological activity. This project's specific aims are to identify a minimal active sequence within each of the two peptides, to build peptide 1 - peptide 4 hybrids with novel chemistry and via cyclic analogs, to define the structure-activity relationships and to establish efficacy in inhibiting platelet adhesion in vitro. Optimized compounds resulting from these studies are expected to have biological properties suitable for validation of the F11R inhibition strategy in animal models of cardiovascular disease and as leads for the development of new therapeutics. PUBLIC HEALTH RELEVANCE: The proposed research will help define a novel approach to the treatment of cardiovascular diseases such as atherosclerosis, thrombosis, stroke, and heart attack. New compounds that inhibit platelet adhesion to the inflamed endothelium, mediated by the protein F11R found on both platelets and damaged blood vessel walls, will be designed and synthesized. New peptide inhibitors of F11R that may be suitable for use as therapeutic drugs will be developed and characterized in this research.